The connection between Wnt/[unreadable]-catenin or "canonical" Wnt signaling and cancer is well appreciated. Some cancers, such as colon cancer, have mutations in components of the signaling pathway (i.e. adenomatous polyposis coli protein, "APC", axin, and [unreadable]-catenin). Others have upregulated signaling due to methylation of promoters driving expression of secreted signaling inhibitors such as sFRP or DKK1. Still others have upregulated expression of Wnts or their receptors. In breast cancer and some leukemias, cancer stem cell maintenance has been shown to depend on Wnt signaling. Both [unreadable]-catenin dependent and independent signaling pathways are implicated in stem cell maintenance. It is unclear in most cases exactly how Wnt signaling is upregulated in cancer stem cells. However, in the more overtly Wnt dependent cancers, it is clear that intervention at multiple points in the signaling pathway(s) is required for effective treatment of a broad range of cancers. We have developed and validated a cell based screen for inhibitors of Wnt signaling which can identify inhibitors throughout the entire pathway including secretion from Wnt expressing cells. We have also characterized a series of secondary assays which can place the function of each inhibitor within one of six defined portions or compartments of the signaling pathway. Through high throughput screening, we hope to identify inhibitors in each compartment and characterize them in a broad range of cancer cell based assays. We propose to identify inhibitors of Wnt signaling effectors throughout the signaling cascade, from Wnt secretion to transcription of target genes, and identify their targets and epistatic locations. Much accumulated evidence implicates both [unreadable]-catenin dependent and independent Wnt signaling in overtly Wnt dependent cancers and cancer stem cell self renewal. With these compounds we propose to identify targets with the highest therapeutic indices and efficacy for treatment of Wnt dependent cancers. [unreadable] [unreadable] [unreadable]